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Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function.

ABSTRACT: Dilated cardiomyopathy (DCM) leads to heart failure, a leading cause of death in industrialized nations. Approximately 30% of DCM cases are genetic in origin, with some resulting from point mutations in cardiac myosin, the molecular motor of the heart. The effects of these mutations on myosin's molecular mechanics have not been determined. We have engineered two murine models characterizing the physiological, cellular, and molecular effects of DCM-causing missense mutations (S532P and F764L) in the alpha-cardiac myosin heavy chain and compared them with WT mice. Mutant mice developed morphological and functional characteristics of DCM consistent with the human phenotypes. Contractile function of isolated myocytes was depressed and preceded left ventricular dilation and reduced fractional shortening. In an in vitro motility assay, both mutant cardiac myosins exhibited a reduced ability to translocate actin (V(actin)) but had similar force-generating capacities. Actin-activated ATPase activities were also reduced. Single-molecule laser trap experiments revealed that the lower V(actin) in the S532P mutant was due to a reduced ability of the motor to generate a step displacement and an alteration of the kinetics of its chemomechanical cycle. These results suggest that the depressed molecular function in cardiac myosin may initiate the events that cause the heart to remodel and become pathologically dilated.

SUBMITTER: Schmitt JP

PROVIDER: S-EPMC1599993 | biostudies-literature | 2006 Sep

REPOSITORIES: biostudies-literature

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Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function.

Schmitt Joachim P JP Debold Edward P EP Ahmad Ferhaan F Armstrong Amy A Frederico Andrea A Conner David A DA Mende Ulrike U Lohse Martin J MJ Warshaw David D Seidman Christine E CE Seidman J G JG

Proceedings of the National Academy of Sciences of the United States of America 20060918 39

Dilated cardiomyopathy (DCM) leads to heart failure, a leading cause of death in industrialized nations. Approximately 30% of DCM cases are genetic in origin, with some resulting from point mutations in cardiac myosin, the molecular motor of the heart. The effects of these mutations on myosin's molecular mechanics have not been determined. We have engineered two murine models characterizing the physiological, cellular, and molecular effects of DCM-causing missense mutations (S532P and F764L) in ...[more]

PMID: 16983074

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Project description:Heart failure (HF) is a worldwide pandemic with an unacceptable high level of morbidity and mortality. Understanding the different pathophysiological mechanisms will contribute to prevention and individualized therapy of HF. We established mouse models for ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) by inducing myocardial infarction (MI) and Coxsackievirus B3 infection, respectively. Isobaric tags for relative and absolute quantitation and liquid chromatography coupled with tandem mass spectrometry technology was used to identify the protein expression profiles in control and failing hearts. A total of 1,638 proteins were identified and compared in this proteomics analysis. Among them, 286 proteins were differently expressed. Gene ontology, KEGG pathway and ingenuity pathway analysis was performed to systematically assess the potential connections of the differentially expressed proteins to biological functions. Compared with control group, the differentially expressed proteins derived from the hearts of ICM and DCM mice were partially similar and mainly modulated in oxidative phosphorylation, metabolism and protein folding pathways. Moreover, difference still existed, the differentially expressed proteins between DCM and ICM hearts were significantly modulated in oxidative phosphorylation, metabolic and AMPK signaling pathways. Confirmatory western bolt analysis demonstrated that SDHB was down-regulated in both ICM and DCM hearts, while UQCRQ, GLUT4 and adiponectin were up-regulated in ICM hearts. Adenosine triphosphate (ATP) concentration significantly decreased in both DCM and ICM hearts. The protein expression of phospho-AMPKα decreased significantly in DCM hearts, but increased in ICM. In summary, oxidative phosphorylation, cardiac metabolism, and protein folding play critical roles in the pathogenesis of HF. The diverse changes in protein expression profiles between failing hearts induced by either MI or CVB3 infection demonstrated the heterogeneity of HF. Understanding the differences in proteome profiles could offer more precise therapeutic options for HF.

Dataset Information

Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function.

Publications

Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function.

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